Efficacy and Safety of Ornithine Phenylacetate for Treating Overt Hepatic Encephalopathy in a Randomized Trial
Efficacy and Safety of Ornithine Phenylacetate for Treating Overt Hepatic Encephalopathy in a Randomized Trial
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DOI：
10.1016/j.cgh.2020.10.019
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发表时间：
2021-11-11
影响因子：
12.6
通讯作者：
Bajaj，Jasmohan S.
中科院分区：
文献类型：
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作者：
Rahimi，Robert S.;Safadi，Rifaat;Bajaj，Jasmohan S.
背景与目的肝性脑病（HE）与发病率、死亡率和医疗资源使用的增加有关.在这项2b期研究中，我们评估了鸟氨酸苯乙酸盐（OP）（一种氨清除剂）在肝硬化住院患者中的疗效和安全性，筛选时氨水平升高，以及急性或明显的HE。截止2016年12月29日患者被随机分配到接受安慰剂或OP（10，15或20 g/天，基于肝病的严重程度）的组，加上每个机构的标准治疗（例如，乳果糖，以实现2-3次排便，有或没有利福昔明，根据指南）。主要终点是至确认临床应答的时间，定义为意向治疗人群中从基线HEST 3/4期降低至HEST 2期或从基线2期改善至HEST 0/1期（所有患者在筛选时氨水平升高，由当地实验室确定）。结果根据当地实验室的氨测量，OP组与安慰剂组之间无显著差异（P= 0.129）。中心实验室分析证实，基线时氨水平升高（n=201）显示，OP组与安慰剂组相比，HE临床改善中位时间提前21小时。发生任何特定不良事件的患者百分比在两组之间没有显著差异。严重不良事件发生在25%的患者在OP组和29%的安慰剂组（P=.552）。结论在随机对照试验的肝硬化和HE患者，我们发现没有显着差异的时间，以临床改善患者给予OP与安慰剂之间。然而，OP似乎是安全的，应该在接受急性或明显HE潜在促发剂治疗的住院患者中进行进一步的高氨血症治疗试验。ClinicalTrials.gov编号：NCT 01966419
Background & AimsHepatic encephalopathy (HE) is associated with increased morbidity, mortality, and healthcare resource use. In this phase 2b study, we evaluated the efficacy and safety of ornithine phenylacetate (OP), an ammonia scavenger, in hospitalized patients with cirrhosis, increased levels of ammonia at screening, and acute or overt HE.MethodsWe conducted a double-blind study of 231 patients with cirrhosis and HE at multiple sites in North America, Europe, Israel, and Australia from January 7, 2014, through December 29, 2016. Patients were randomly assigned to groups that received placebo or OP (10, 15, or 20 g/day, based on severity of liver disease), plus each institution’s standard of care (for example, lactulose to achieve 2–3 bowel movements with or without rifaximin, in accordance with guidelines). The primary endpoint was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stage 3/4 or improvement to HEST stage 0/1 from baseline stage 2, in the intent to treat population (all patients with increased levels of ammonia at screening, determined by a local laboratory).ResultsMedian times to clinical improvement, based on ammonia measurements at local laboratories, did not differ significantly between the groups given OP vs the placebo group (P=.129). Analyses of central laboratory confirmed increases in levels of ammonia at baseline (n=201) revealed a clinical improvement in HE at a median of 21 hours sooner in groups given OP vs placebo. The percentages of patients with any specific adverse event did not differ significantly between groups. Serious adverse events occurred in 25% of patients in the OP group and 29% in the placebo group (P=.552).ConclusionsIn a randomized controlled trial of patients with cirrhosis and HE, we found no significant difference in time to clinical improvement between patients given OP vs placebo. However, OP appears to be safe and should undergo further testing for treatment of hyperammonemia in hospitalized patients receiving treatment for the underlying precipitant of acute or overt HE. ClinicalTrials.gov no: NCT01966419